title: Increase in net activity of serine proteinases but not gelatinases after local endotoxin exposure in the peripheral airways of healthy subjects.
abstract: We tested the hypothesis that activation of the innate immune response induces an imbalance in the proteolytic homeostasis in the peripheral airways of healthy subjects, towards excess serine or gelatinase proteinase activity. During bronchoscopy, 18 healthy human subjects underwent intra-bronchial exposure to endotoxin and contra-lateral exposure to vehicle. Bronchoalveolar lavage (BAL) samples were harvested 24 or 48 hours (h) later. We quantified archetype proteinases, anti-proteinases, inflammatory BAL cells, and, importantly, total plus net proteinase activities using functional substrate assays. As expected, endotoxin exposure increased the concentrations of polymorphonuclear leukocytes (PMN's) and macrophages, of proteinases and the anti-proteinases tissue inhibitor of metalloproteinase-1, α-1-antitrypsin and, to a lesser extent, secretory leukoproteinase inhibitor, at both time points. Notably, at these time points, endotoxin exposure substantially increased the quantitative NE/SLPI ratio and the net serine proteinase activity corresponding to neutrophil elastase (NE). Endotoxin exposure also increased the total gelatinase activity corresponding to matrix metalloproteinase (MMP)-9; an activity dominating over that of MMP-2. However, endotoxin exposure had no impact on net gelatinolytic activity at 24 or 48 h after exposure. Thus, local activation of the innate immune response induces an imbalance towards increased net serine proteinase activity in the proteolytic homeostasis of the peripheral airways in healthy subjects. Hypothetically, this serine proteinase activity can contribute to tissue remodelling and hypersecretion via NE from PMN's, if it is triggered repeatedly, as might be the case in chronic inflammatory airway disorders.
authors.affiliation: Lung Immunology Group, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Margaretha E
authors.initials: ME
authors.lastname: Smith
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.forename: Carina
authors.initials: C
authors.lastname: Malmhäll
authors.forename: Margareta
authors.initials: M
authors.lastname: Sjöstrand
authors.forename: Pernilla
authors.initials: P
authors.lastname: Glader
authors.forename: Per
authors.initials: P
authors.lastname: Venge
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Anders
authors.initials: A
authors.lastname: Lindén
authors.forename: Ingemar
authors.initials: I
authors.lastname: Qvarfordt
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D057057:Serine Proteases / Q000378:metabolism*; D012995:Solubility; D055815:Young Adult
chemical_list: D004731:Endotoxins; D057057:Serine Proteases; D019272:Leukocyte Elastase; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9